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Repair by connective tissue
Overview
• Severe or persistent tissue injury with damage both
to parenchymal cells and to the stromal framework
leads to a situation in which repair cannot be
accomplished by parenchymal regeneration alone.
• Repair occurs by replacement of the non
regenerated parenchymal cells with connective
tissue.
INTRODUCTION
• Scar - formed as part of healing process following
damage to skin as body lays down collagen fibres
• If epithelial layer alone is damaged, there is often
little or no scarring - as it heals by regeneration.
• If dermal layer is damaged - healing is by repair.
• Scar revision - plastic surgery performed to
improve condition /appearance of scar anywhere
on body.
• Scar evaluation& revision techniques are chief
among most important skills in facial plastic and
reconstructive surgeon's armamentarium.
 General components of this process are:
 Formation of new blood vessels (Angiogenesis)
 Migration and proliferation of fibroblast
 Deposition of ECM
 Maturation and reorganization of the fibrous
tissue (Remodeling)
WOUND HEALING
CELLULAR ACTIVITY
Angiogenesis from endothelial
precursors
 Common precursor: hemangioblast that gives rise
to angioblast and hematopoietic stem cells.
 Angioblasts then proliferate and differentiate into
endothelial cells that form arteries,veins and
lymphatics.
 ABCs (angioblast like cells) in the bone marrow can
be recruited into tissues to initiate angiogenesis.
 What is VASCULOGENESIS?
Angiogenesis from preexisting vessel
• Vasodilation in response to nitric acid and VEGF.
• Increased permeability of pre-existing vessel.
• Proteolytic degradation of the parent vessel BM by
metalloproteinases and disruption of cell to cell
contact btw endothelial cells of the vessel by
plasminogen activator.
• Migration of endothelial cells from the original
capillary toward an angiogenic stimulus.
• Proliferation of the endothelial cells behind
the leading edge of migrating cells.
• Maturation of endothelial cells with inhibition
of growth and organization into capillary
tubes.
• Recruitment and proliferation of pericytes (for
capillaries) and smooth muscle cells (for larger
vessel) to support the endothelial tube.
Growth factors and receptors involved
in angiogenesis
VEGF secreted by mesenchymal cells and stromal
cells.
Angiopoietins(Ang1 and Ang2)
FGF-2
PDGF
TGF-B
Angiopoietins ,PDGF,TGF-B participate in the
stabilization process,
PDGF participates in the recruitmenmt of the
smooth muscle cells,
TGF-b stabilizes newly formed vessel by
enhancing the production Of ECM
production.
ECM proteins as REGULATORS OF
ANGIOGENESIS
• Integrins ,
• Thrombospondin 1 and SPARC, tenascin
C,destabilize cell matrix interactions and
promote angiogenesis.
• Proteinases , plasminogen activators and
matrix metalloproteinases : important role in
tissue remodeling during endothelial invasion.
Scar formation
• Emigration and proliferation of fibroblasts in
the site of injury
• Deposition of ECM
• Tissue remodeling
Fibroblast Migration and Proliferation
• Exudation and deposition of plasma protein,
fibrinogen and plasma fibronectin in the ECM
of granulation tissue provides a provisional
stroma for fibroblasts and endothelial cell
ingrowth.
• Migration of fibroblasts to the site of injury
and subsequent proliferation are triggered by
multiple growth factors TGF-B, PDGF, EGF, FGF
and the cytokines IL-1 and TNF
ECM Deposition and Scar Formation
• TGF-B appears to be the most important
because of the multitude of effects that favors
fibrous tissue deposition.
• It is produced by most of the cells in
granulation tissue and causes fibroblast
migration and proliferation, increased
synthesis of collagen and fibronectin and
decreased degradation of ECM by
metalloproteinases.
• Fibrillar collagens form a major portion of the
connective tissue in repair sites and
development of strength in healing wounds
• As the scar matures, vascular regression
continues, eventually transforming the richly
vascularized granulation tissue into a pale,
avascular scar
Scar Classification
• Mature scar
• Immature scar
• Linear hypertrophic scar
• Widespread hypertrophic
• Minor keloid
• Major keloid
• Contractures
• Superficial macular scars
• Ice pick scar
• Rolling scars
• Boxcar scars
• Mature scar - light-colored, flat scar.
• Immature scar - red, sometimes itchy or painful and slightly
elevated scar in the process of remodeling. Many of these will
mature normally over time and become flat
• Linear hypertrophic (e.g surgical/traumatic) scar- red, raised,
sometimes itchy scar confined to the border of original
surgical incision occurring within weeks following surgery &
can regress of its own
• Widespread hypertrophic (e.g., burn) scar—A widespread red,
raised, sometimes itchy scar that remains within the borders
of the burn injury.
• Minor keloid - focally raised, itchy scar extending over normal
tissue & may develop up to 1 year after injury and does not
regress on its own
• Major keloid - large, raised (0.5 cm) scar, possibly painful /
pruritic extending over normal tissue often resulting from
minor trauma and can continue to spread over years.
• Contractures - restrict movement due to skin & underlying
tissue that pull together during healing and can occur when
there is a large amount of tissue loss or where a wound
crosses a joint.
• Superficial macular scars: occur only if epidermis & superficial
dermis are involved.
 appear as erythematous/pigmented macules
• Ice pick scars (cone-shaped): narrow, deep & sharply marginated
epithelial tracts extend vertically to deep dermis or subcutaneous
tissue.
• Rolling scars (wavy): occur from dermal tethering of otherwise
relatively normal appearing skin.
 Abnormal fibrous anchoring of dermis to subcutis lead to
superficial shadowing & rolling or undulating appearance
t0 the overlying skin
• Boxcar scars (chicken pox scar like): round to oval depressions with
sharply demarcated vertical edges, similar to varicela scars.
 Are clinically wider at the surface than ice pick scars and
do taper to a point at the base
Tissue Remodeling
• The balance between ECM synthesis and
degradation results in remodeling of the CT
framework.
• Degradation of collagen and other ECM
proteinS is achieved by a family of matrix
metalloproteinases which are dependant on
zinc ions for their activity.
• MMPs include interstitial collagenases (MMP1, 2, 3) which
cleave the fibrillar collagen type 1, 2 and 3
• Gelatinases (MMP2 and 9) degrade amorphous collagens and
fibronectin.
• Stromelysin (MMP-3,10,11) act on proteoglycan ,
laminin,fibronectin,amorphous collagen.
• MMPS are synthesized as propeptides that require proteolytic
cleavage for activation.
• Their secretion is induced by certain stimuli such as growth
factors,cytokines,phagocytosis,physical stress and is inhibited
by TGF-b and steroids
• Collagenases are synthesized in as a latent
precursor (procollagenase) that is activated by
chemicals such as free radicals produced in
oxidative burst of leukocytes and proteinases
• Once formed activated collagenases are
rapidly inhibited by a family of specific tissue
inhibitor of metalloproteinases (TIMP).
WOUND HEALING
• Cutaneous wound healing is divided into three
phases
• Inflammation (early and late)
• Granulation tissue formation and
reepithilialization
• Wound contraction ,ECM deposition and
remodeling.
• Wound healing is a fibroproliferative response
that is mediated through growth factors and
cytokines.
• Skin wounds are classically described to heal
by primary or secondary intention.
Healing by first intention (wounds with
opposed edges)
• Common example of wound repair is healing
of a clean, uninfected surgical wound
approximated by sutures. such healing is
called as primary union or healing by first
intention.
• Incision causes,
• Death of limited number of epithelial cells and
connective tissue.
• Disruption of epithelial BM.
Process
• Within 24 hours;
• Neutrophils appear at the margin of the
incision moving towards the fibrin clot.
• In 24 to 48 hours;
• Movement of the epithelial cells from wound
edges from dermis cut margins depositing BM
components as they move
• Day 3;
• Neutrophils are replaced by macrophages.
• Invasion of granulaton tissue invading the
incision space.
• Collagen fibers are present in the margin of
the incision but does not bridge the incision.
• Epithelial cell proliferation thickens the
epidermal layer
• Day5;
• Incisional space filled with granulation tissue.
• Neovascularization is maximal
• Abundant collagen fibers ,bridging the
incision.
• Mature epidermal architecture with surface
kertinization.
• Second week;
• Continued accumulation of collagen and proliferation
of fibroblast .
• Dissapperance of edema ,leukocyte infiltrate, and
increased vascularity.
• End of first month;
• Scar is made of cellular C.T inflammatory cell
infilterate , covered now by intact epidermis.
• Dermal appendages that have been destroyed in the
line of incision are permanently lost.
Healing by second intention (wound
with separate edges)
extensive loss of cells and tissue.
Large defects.
Abundant granulation tissue grows in from the
margin to complete the repair
Difference
• Larger tissue defect
• Larger fibrin clot
• More necrotic debris and exudate
• Inflammatory reaction is more intense.
• Abundant granulation tissue is formed
Wound contraction
• Formation of a network of actin containing
fibroblasts at the edge of the wound.
• Permanent wound contraction requires the
action of myofibroblasts.
• Contraction of these cells at the wound site
decreases the gap between the dermal edges
of the wound.
Wound strength
• When sutures are removed at the end of the
first week ,strength is approximately 10% that
of unwounded skin, but strength increases
rapidly over the next 4 wks.
• At the end of third month it the rate decreases
and the wound strength is about 70 to80% of
the unwounded skin.
Factors that influence wound healing
• Systemic factors;
• Nutrition (protein def,Zn, vit.C def) inhibit
collagen synthesis
• Metabolic status, diabetes mellitis ,delayed
wound healing, ( microangiopathy)
• Inadequate B.S (arteriosclerosis, varicose
veins)
• Hormones. ( glucocorticoids)
Local factors
• Infection (persistent tissue injury and
inflammation)
• Mechanical factors ,(mobility ,compression of
B.V)
• Foreign bodies, (sutures ,fragments of bone,
steel or glass)
Localization and size of wound (face, foot)
Complications
Inadequate formation of granulation tissue.
Wound dehiscence
• Rupture of a wound is most common after
abdominal surgery and is due to increased
abdominal pressure
• Vomiting, coughing , ileus
• Exuberant granulation is another deviation in
wound healing consisting of the formation of
excessive amounts of granulation tissue,
which protrudes above the level of the
surrounding skin and blocks re-
epithelialization called proud flesh.
• Ulceration of the wounds because of
inadequate vascularization during healing.
(peripheral vascular diseases)
• Non healing wounds are also found in areas of
denervation. (diabetic peripheral neuropathy)
Excessive formation of the
components of the repair
• Excessive amount of collagen lead to
hypertrophic scar.
• Is a raised scar
• Keloid ,it is a scar tissue which goes beyond
the boundaries of the original wound and
does not regress.
• Incisional scars or traumatic injuries may be
followed by exuberant proliferation of
fibroblasts and other connective tissue
elements that may recur after excision.
Called desmoids, or aggressive fibromatoses,
these lie in the interface between benign
proliferations and malignant (though low-
grade) tumors.
• Contracture
• Exaggeration in the process of contraction in
the wound is called contracture.
• Severe burns
• Palms,soles.thorax
• Healing wounds may also generate excessive
granulation tissue that protrudes above the
level of the surrounding skin and in fact
hinders re-epithelialization. This is called
exuberant granulation, or proud flesh, and
restoration of epithelial continuity requires
cautery or surgical resection of the
granulation tissue.
Thank you,

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Pathology healing and repair stmu

  • 2. Overview • Severe or persistent tissue injury with damage both to parenchymal cells and to the stromal framework leads to a situation in which repair cannot be accomplished by parenchymal regeneration alone. • Repair occurs by replacement of the non regenerated parenchymal cells with connective tissue.
  • 3. INTRODUCTION • Scar - formed as part of healing process following damage to skin as body lays down collagen fibres • If epithelial layer alone is damaged, there is often little or no scarring - as it heals by regeneration. • If dermal layer is damaged - healing is by repair. • Scar revision - plastic surgery performed to improve condition /appearance of scar anywhere on body. • Scar evaluation& revision techniques are chief among most important skills in facial plastic and reconstructive surgeon's armamentarium.
  • 4.
  • 5.  General components of this process are:  Formation of new blood vessels (Angiogenesis)  Migration and proliferation of fibroblast  Deposition of ECM  Maturation and reorganization of the fibrous tissue (Remodeling)
  • 8. Angiogenesis from endothelial precursors  Common precursor: hemangioblast that gives rise to angioblast and hematopoietic stem cells.  Angioblasts then proliferate and differentiate into endothelial cells that form arteries,veins and lymphatics.  ABCs (angioblast like cells) in the bone marrow can be recruited into tissues to initiate angiogenesis.  What is VASCULOGENESIS?
  • 9. Angiogenesis from preexisting vessel • Vasodilation in response to nitric acid and VEGF. • Increased permeability of pre-existing vessel. • Proteolytic degradation of the parent vessel BM by metalloproteinases and disruption of cell to cell contact btw endothelial cells of the vessel by plasminogen activator. • Migration of endothelial cells from the original capillary toward an angiogenic stimulus.
  • 10. • Proliferation of the endothelial cells behind the leading edge of migrating cells. • Maturation of endothelial cells with inhibition of growth and organization into capillary tubes. • Recruitment and proliferation of pericytes (for capillaries) and smooth muscle cells (for larger vessel) to support the endothelial tube.
  • 11.
  • 12.
  • 13. Growth factors and receptors involved in angiogenesis VEGF secreted by mesenchymal cells and stromal cells. Angiopoietins(Ang1 and Ang2) FGF-2 PDGF TGF-B
  • 14. Angiopoietins ,PDGF,TGF-B participate in the stabilization process, PDGF participates in the recruitmenmt of the smooth muscle cells, TGF-b stabilizes newly formed vessel by enhancing the production Of ECM production.
  • 15. ECM proteins as REGULATORS OF ANGIOGENESIS • Integrins , • Thrombospondin 1 and SPARC, tenascin C,destabilize cell matrix interactions and promote angiogenesis. • Proteinases , plasminogen activators and matrix metalloproteinases : important role in tissue remodeling during endothelial invasion.
  • 16. Scar formation • Emigration and proliferation of fibroblasts in the site of injury • Deposition of ECM • Tissue remodeling
  • 17. Fibroblast Migration and Proliferation • Exudation and deposition of plasma protein, fibrinogen and plasma fibronectin in the ECM of granulation tissue provides a provisional stroma for fibroblasts and endothelial cell ingrowth. • Migration of fibroblasts to the site of injury and subsequent proliferation are triggered by multiple growth factors TGF-B, PDGF, EGF, FGF and the cytokines IL-1 and TNF
  • 18. ECM Deposition and Scar Formation • TGF-B appears to be the most important because of the multitude of effects that favors fibrous tissue deposition. • It is produced by most of the cells in granulation tissue and causes fibroblast migration and proliferation, increased synthesis of collagen and fibronectin and decreased degradation of ECM by metalloproteinases.
  • 19. • Fibrillar collagens form a major portion of the connective tissue in repair sites and development of strength in healing wounds • As the scar matures, vascular regression continues, eventually transforming the richly vascularized granulation tissue into a pale, avascular scar
  • 20. Scar Classification • Mature scar • Immature scar • Linear hypertrophic scar • Widespread hypertrophic • Minor keloid • Major keloid • Contractures • Superficial macular scars • Ice pick scar • Rolling scars • Boxcar scars
  • 21. • Mature scar - light-colored, flat scar. • Immature scar - red, sometimes itchy or painful and slightly elevated scar in the process of remodeling. Many of these will mature normally over time and become flat • Linear hypertrophic (e.g surgical/traumatic) scar- red, raised, sometimes itchy scar confined to the border of original surgical incision occurring within weeks following surgery & can regress of its own
  • 22. • Widespread hypertrophic (e.g., burn) scar—A widespread red, raised, sometimes itchy scar that remains within the borders of the burn injury. • Minor keloid - focally raised, itchy scar extending over normal tissue & may develop up to 1 year after injury and does not regress on its own • Major keloid - large, raised (0.5 cm) scar, possibly painful / pruritic extending over normal tissue often resulting from minor trauma and can continue to spread over years. • Contractures - restrict movement due to skin & underlying tissue that pull together during healing and can occur when there is a large amount of tissue loss or where a wound crosses a joint.
  • 23. • Superficial macular scars: occur only if epidermis & superficial dermis are involved.  appear as erythematous/pigmented macules • Ice pick scars (cone-shaped): narrow, deep & sharply marginated epithelial tracts extend vertically to deep dermis or subcutaneous tissue. • Rolling scars (wavy): occur from dermal tethering of otherwise relatively normal appearing skin.  Abnormal fibrous anchoring of dermis to subcutis lead to superficial shadowing & rolling or undulating appearance t0 the overlying skin
  • 24. • Boxcar scars (chicken pox scar like): round to oval depressions with sharply demarcated vertical edges, similar to varicela scars.  Are clinically wider at the surface than ice pick scars and do taper to a point at the base
  • 25. Tissue Remodeling • The balance between ECM synthesis and degradation results in remodeling of the CT framework. • Degradation of collagen and other ECM proteinS is achieved by a family of matrix metalloproteinases which are dependant on zinc ions for their activity.
  • 26. • MMPs include interstitial collagenases (MMP1, 2, 3) which cleave the fibrillar collagen type 1, 2 and 3 • Gelatinases (MMP2 and 9) degrade amorphous collagens and fibronectin. • Stromelysin (MMP-3,10,11) act on proteoglycan , laminin,fibronectin,amorphous collagen. • MMPS are synthesized as propeptides that require proteolytic cleavage for activation. • Their secretion is induced by certain stimuli such as growth factors,cytokines,phagocytosis,physical stress and is inhibited by TGF-b and steroids
  • 27. • Collagenases are synthesized in as a latent precursor (procollagenase) that is activated by chemicals such as free radicals produced in oxidative burst of leukocytes and proteinases • Once formed activated collagenases are rapidly inhibited by a family of specific tissue inhibitor of metalloproteinases (TIMP).
  • 28. WOUND HEALING • Cutaneous wound healing is divided into three phases • Inflammation (early and late) • Granulation tissue formation and reepithilialization • Wound contraction ,ECM deposition and remodeling.
  • 29. • Wound healing is a fibroproliferative response that is mediated through growth factors and cytokines. • Skin wounds are classically described to heal by primary or secondary intention.
  • 30. Healing by first intention (wounds with opposed edges) • Common example of wound repair is healing of a clean, uninfected surgical wound approximated by sutures. such healing is called as primary union or healing by first intention.
  • 31. • Incision causes, • Death of limited number of epithelial cells and connective tissue. • Disruption of epithelial BM.
  • 32. Process • Within 24 hours; • Neutrophils appear at the margin of the incision moving towards the fibrin clot. • In 24 to 48 hours; • Movement of the epithelial cells from wound edges from dermis cut margins depositing BM components as they move
  • 33. • Day 3; • Neutrophils are replaced by macrophages. • Invasion of granulaton tissue invading the incision space. • Collagen fibers are present in the margin of the incision but does not bridge the incision. • Epithelial cell proliferation thickens the epidermal layer
  • 34.
  • 35. • Day5; • Incisional space filled with granulation tissue. • Neovascularization is maximal • Abundant collagen fibers ,bridging the incision. • Mature epidermal architecture with surface kertinization.
  • 36. • Second week; • Continued accumulation of collagen and proliferation of fibroblast . • Dissapperance of edema ,leukocyte infiltrate, and increased vascularity. • End of first month; • Scar is made of cellular C.T inflammatory cell infilterate , covered now by intact epidermis. • Dermal appendages that have been destroyed in the line of incision are permanently lost.
  • 37. Healing by second intention (wound with separate edges) extensive loss of cells and tissue. Large defects. Abundant granulation tissue grows in from the margin to complete the repair
  • 38.
  • 39.
  • 40. Difference • Larger tissue defect • Larger fibrin clot • More necrotic debris and exudate • Inflammatory reaction is more intense. • Abundant granulation tissue is formed
  • 41.
  • 42. Wound contraction • Formation of a network of actin containing fibroblasts at the edge of the wound. • Permanent wound contraction requires the action of myofibroblasts. • Contraction of these cells at the wound site decreases the gap between the dermal edges of the wound.
  • 43. Wound strength • When sutures are removed at the end of the first week ,strength is approximately 10% that of unwounded skin, but strength increases rapidly over the next 4 wks. • At the end of third month it the rate decreases and the wound strength is about 70 to80% of the unwounded skin.
  • 44.
  • 45. Factors that influence wound healing • Systemic factors; • Nutrition (protein def,Zn, vit.C def) inhibit collagen synthesis • Metabolic status, diabetes mellitis ,delayed wound healing, ( microangiopathy) • Inadequate B.S (arteriosclerosis, varicose veins) • Hormones. ( glucocorticoids)
  • 46. Local factors • Infection (persistent tissue injury and inflammation) • Mechanical factors ,(mobility ,compression of B.V) • Foreign bodies, (sutures ,fragments of bone, steel or glass) Localization and size of wound (face, foot)
  • 47. Complications Inadequate formation of granulation tissue. Wound dehiscence • Rupture of a wound is most common after abdominal surgery and is due to increased abdominal pressure • Vomiting, coughing , ileus
  • 48. • Exuberant granulation is another deviation in wound healing consisting of the formation of excessive amounts of granulation tissue, which protrudes above the level of the surrounding skin and blocks re- epithelialization called proud flesh.
  • 49. • Ulceration of the wounds because of inadequate vascularization during healing. (peripheral vascular diseases) • Non healing wounds are also found in areas of denervation. (diabetic peripheral neuropathy)
  • 50. Excessive formation of the components of the repair • Excessive amount of collagen lead to hypertrophic scar. • Is a raised scar • Keloid ,it is a scar tissue which goes beyond the boundaries of the original wound and does not regress.
  • 51.
  • 52.
  • 53. • Incisional scars or traumatic injuries may be followed by exuberant proliferation of fibroblasts and other connective tissue elements that may recur after excision. Called desmoids, or aggressive fibromatoses, these lie in the interface between benign proliferations and malignant (though low- grade) tumors.
  • 54.
  • 55. • Contracture • Exaggeration in the process of contraction in the wound is called contracture. • Severe burns • Palms,soles.thorax
  • 56.
  • 57. • Healing wounds may also generate excessive granulation tissue that protrudes above the level of the surrounding skin and in fact hinders re-epithelialization. This is called exuberant granulation, or proud flesh, and restoration of epithelial continuity requires cautery or surgical resection of the granulation tissue.